Single stable dose vaccinator



Nov. 7, 1967 H. KRAVITZ v 3,351,059

SINGLE STABLE DOSE VACCINATOR Filed June 2, 1964 Ff/51j.

; 'Bay g2/V, mm

jf/MW/ @ya United States Patent 3,351,059 SINGLE STABLE DGSE VACCINATR Harvey Kravitz, Skokie, Ill., assignor of one-half to Norman Lettvin, Highland Park, Ill. Filed .lune 2, 1964, Ser. No. 371,918 2 Claims. (Cl. 12S-253) This application is a continuation-in-part of my copending application on Vaccinating Devices, Serial No. Y

46,730 filed Aug. 1, 1960, now Patent No. 3,136,314.

This invention relates to an improved vaccinator and more particularly relates to a single stable dose vaccinator.

Multiple-point vaccinators, whether they be of the scratch type or of the pressure-puncture type are well known, such as, for example, disclosed in Patent No. 2,817,336. In my said co-pending application of which this application is a continuation-in-part, it is pointed out that when the improved multiple-pressure-puncture instrument that is common to this application is used, a high percentage of takes is achieved, the scar produced is of limited area, precise control without drawing blood is afforded, a novel way of loading the liquid vaccine onto the points is afforded, a less complicated and more rapidly useable instrument is achieved, and utility in using the same type of instrument in applying other biologicals to the skin under test conditions is capable of being attained.

Now, Patent No. 2,817,336 discloses, in one form thereof, the combination of a multiple point scarifier and liquid biological carried thereby to be applied to the selected skin area from the exterior of the scarifier points. My said co-pending application also discloses a multiple point scarilier and liquid biological to be applied to a selected skin area from the scarifying points, with one improvement being that the scarifying points are clustered very closely together, so that the liquid biological may be loaded onto the points to be retained there by surface tension prior to use of the scarifying instrument.

While the said improvements outlined hereinabove are, in themselves, desirable advances over the existing technology, the fact is that there still exist some limitations associated with the foregoing instruments. Thus, both instruments are intended to utilize liquid biologicals. But

in the case of certain liquid biologicals, such as, for

example, smallpox vaccine, the liquid has a relatively limited shelf life of about 90 days, and then only when maintained refrigerated. A dried, or lyophilized, smallpox vaccine would have a much longer shelf life, of about 18 months when in dried state, and furthermore does not have to be refrigerated until after reactivation by a liquid diluent. However, the apparent desired utility of dried biologicals, such as lyophilized smallpox vaccine, itself poses many problems.

Now, the broad concept of providing a single instrument that includes both a scarier and a dried biological on the instrument is old as, for example, wherein a multiple point scratch scarier was provided, and dried virus was carried on the handle of the instrument from which the multiple scarifier points projected. Not only does the location of the dried virus on the holder for the points pose problems in handling by the doctor and possible contamination, but that disclosure contemplated the necessity of wetting of the dried virus with lymph or blood serially resulting from use of the scarier.

Others have prospectively suggested use of dried virus with multiple puncture scariers that are not intended to draw blood, but to my knowledge no one has ever heretofore demonstrated or reported practical effectiveness of such a device. Others have disclosed utilizing relatively widely spaced scarifying needles which in- 3,351,059 Patented Nov. 7, 1967 ice dividually carry thereon dried biologicals, or antigens, but in such constructions the needles have had to be specially treated to pit or scarify the needles to provide interstices, or pockets, in the needle to assure deposit and retention of the dried material therein, and in use, the needles must be either rotated, or left embedded in the flesh for suflcient period of time, to permit the generated lymph or blood flow to activate the dried biological. The latter device also suffers from additional expense incident to the necessary surface treatment of the scarifying points, from the necessity of having to rely upon generation of lymph or blood in the wound of the applicatee, from painfulness of application incident to the shape and spacing of the scarifying needles and the twisting action of the embedded needles in the preferred usage, from inability to insure accurate dosage with each of the separate scariers, and from the necessity of relying upon at least four separate scarifiers with separate dosages thereon to insure a satisfactory inoculation.

The object of this invention is to provide an improved single-stable-dose vaccinator, or scariiier device wherein the scarifier provides multiple inexpensive scarification points and which device provides thereon the biological in dried form located precisely where it is to be used, so that application of the biological occurs simultaneously with the effecting of scarication, and ywhich device does not necessarily rely upon generation of lymph or blood to effect reactivation of the dried virus or biological.

Another object of this invention is to provide an improved multiple point scarifying instrument wherein the multiple points are clustered closely together and a dried biological substance, such as virus or antigen, is deposited in crotches defined by pairs of multiple points to provide effective retention and desirable location of the biological substance for ease in re-activation, and in application of, the biological substance, and to effect production of a product that substantially assures uniformity of dosage.

Further objects and advantages of this invention will become apparent as the following description proceeds and the features of novelty which characterize this invention will be pointed out with particularity in the claims annexed to and forming part of this specification.

FIGURE 1 is a greatly enlarged top plan view of one form of the scarifying portion of a vaccinator embodying features of my invention, and shows the rigid pressure base and cluster of puncture points extending therefrom;

FIGURE 2 is a side elevation view of the pressure base and puncture points shown in FIGURE 1;

FIGURE 3 shows use of the device of FIGURE 2 with the puncture points loaded with liquid biological, such as a vaccine, prior to the lyophilization of the biological;

FIGURE 4 shows the device of FIGURE 3 after the liquid biological has been dried by lyophilization, and illustrates the dried biological retained in position between pairs of picture points;

FIGURE 5 is an enlarged elevational view illustrating another form of multiple-point scarifier loaded with lyophilized biological;

FIGURE 6 is a side elevation View of the device in FIGURE 5 taken looking from the right of FIGURE 5;

FIGURE 7 is a bottom plan view of the device of FIGURE 5; and

FIGURE 8 is a side elevation view illustrating a typical i have utility in tuberculin testing and in other processes where a biological substance is intended to be applied to a scarified portion of skin, and where the device for such operation is to be a single-use, discardable instrument having an extended shelf life prior to use that does not require elaborate or uneconomical storage conditions.

Referring now to the drawings, FIGURES 1 and 2 show one basic form of scarifier generally indicated at 18. The scarifier 18 includes a fiat, generally square, pressure base 20' that is thin but relatively rigid. An abruptly projecting platform 22 is located centrally of the square base 20. Projecting transversely from the plane of platform 22 are nine puncture points 24, each of which is in the form of a tapered pyramid, the opposite sides of which have therebetween an included angle of about 12 degrees. The nine puncture points 24 are equally spaced, as shown, and are arranged in a predetermined pattern of three straight rows each containing three points. Certain edges of the bases of the points 24 coincide with the peripheral edge of platform 22. The platform has a square area with an edge dimension in the order of 0.3 centimeter. The extended tips of the puncture points 24 are spaced approximately 0.3 centimeter from the upper side of the pressure base 20, and the height, or thickness, of the platform 22 is approximately one-quarter of the said spacing. The platform serves to prevent smearing of the vaccine during the vaccination.

The arrangement of the platform 22 centrally of pressure base 20 provides a border portion 2l on the base that is of substantially uniform width and completely surrounds the platform 22. Because of the close spacing of the points 24, they are referred to as being clustered centrally of the base 20.

The provision of the border portion 21 insures that the area of the back side of pressure base 20 is many times the area in which the cluster of points 24 is located. The width of the border portion 21 is substantially the same dimension as the edge width of the platform 22, so that the area of base 20 is about nine times the area of the platform 22.

The scarifier thus far disclosed has been found to have unusual properties. It was first observed that the cluster of nine elongated puncture points 247 within a limited square area of less than 0.3 centimeter along a side, provides a considerable amount of surface area both along the sides of the pyramids 24 and at the surface of platform 22 from whence the points 24 project. It has been discovered that when a small amount of vaccine material, such as a portion of a drop, is deposited, or loaded, onto the cluster of points 24, the surface tension between the vaccine and the contacted surfaces of the puncture points 24 and platform 22 is such that the scarifier 18 may be manipulated to any position whatsoever without the vaccine leaving the puncture points. Thus, with vaccine loaded onto it, the scarifier 1S could be turned completely upside down, with the points facing downwardly and the vaccine will not run off the points.

Now, in an attempt to produce a single stable dose vaccinator, it was first considered whether it was possible to mount or apply vaccine in dried form onto a scarifier point. It was discovered that it was not practical to merely attempt to press on or cause a vaccine in dried form to be made to adhere to sacrifier points. The concept of `drying a liquid vaccine in situ on a single, smooth, un-

treated vaccinator point held little promise of success; and this was likewise true in attempting to predict or obtain uniformity of dosage, which is essential if one is to know how much dried vaccine is carried by the instrument.

However, it has been discovered that the aforenoted characteristic of holding liquid vaccine in position on a multiple point scarier assists in providing an operative device. It will be observe-d that each pair of adjacent scarifier points 24 defines therebetween a socket, or crotch 26. The presence of a pair of closely adjacent points 24 4 provides structural elements that greatly enhance in kind, rather than in degree, the effect of capillarity, or reactance to surface tension of a liquid, as compared with the ability of an unassisted single point to similarly utilize the effects of surface tension of a liquid. Thus, each crotch 26 defined by a pair of points 24 may be easily filled, or fully bridged over, -by a load of liquid vaccine V. Then by drying, or lyophilizing, the liquid vaccine V, the dry residue of the drying process remains in the crotch 26 and effects surprisingly greater tenacity to the surfaces of points 24 and to the surface of platform 22 than coul-d be effected by forcing the dried vaccine under pressure into such a crotch 26. Once the multiple-point scarifer has been provided with the residue of a predetermined amount of liquid vaccine retained on and between pairs of points 24, it will be seen that addition of sufcient distilled water, or other diluent, in only an amount to be retained by surface tension on points 24 will provide the same amount of liquid that had disappeared as a result of the drying process, and hence the dried vaccine is capable of being reconstituted in the same dosage and concentration as in the original loading of liquid vaccine prior to a -drying procedure.

With the foregoing principles in mind, multiple point vaccinators of the type herein disclosed where loaded with smallpox vaccine dropped from a pipette onto the points as they faced upwardly. The vaccines used were an avianized vaccine sold commercially by Lederle Laboratories and the liquid vaccine used by Wyeth Laboratories in their production of the product sold under the trademark Dry-Vax. After drying, by lyophilization, as hereinafter described, there was a plug of dried material, V (Dry), located in the interconnecting sockets between adjacent points 24 and against platform 22, similar to that illustrated in FIGURE 4. After reconstitution with a portion of a drop of sterile distilled water, as a diluent, in an amount sufficient to be retained on the points 24 by surface tension, as illustrated in FIGURE 3, successful vaccinations were effected by pressing the multiple points 24 with vaccine loaded thereon against a selected skin area on the individual being vaccinated. The results obtained with use of these devices were identical in character effect, reaction, and all other measurable or observable indicia, as those obtained with use of liquid vaccines. No ill effects were observed. The -devices constructed and tested were efficacious and not harmful.

Loading of the scarier points 24 may be effected either by dropping liquid vaccine onto upwardly facing points, or by dipping downwardly facing points into a bath, or pool, of vaccine and holding it in such position until the capillary action and surface tension has operated to fully load the points with liquid vaccine. The latter process -has been determined to be feasible because the capillarity of the pairs of adjacent points 24 and the liquid tension of the vaccine V will effect loading of the crotches 26 as illustrated in FIGURE 3.

After loading of liquid vaccine V onto the points it is subjected to a lyophilizing process in a refrigerated chamber maintained initially at 40 to *50 C. at atmospheric pressure. A drying period of 24 hours at these conditions is sufficient to insure complete freezing. The chamber is then evacuated and the vaccine dried from the frozen state in vacuo. The chamber temperature is then gradually raised to 0 C. by means of an infrared heat source to complete the drying operation. The chamber is then vented with sterile dry nitrogen. The residual moisture content of the dried vaccine should preferably be less than 1%. FIGURE 4 illustrates the appearance of a multiple-point scarifier with dried vaccine, V (Dry), thereon produced by such a process.

After drying, the device is preferably packaged under aseptic conditions in the presence of dry nitrogen to prevent the dried vaccine from absorbing moisture. The device is, for example, packaged in a heat sealed, or ultrasonic sealed, transparent envelope E, of cellophane or plastic iilm, such as polyethylene or Teflon, containing dry nitrogen gas therein. This type of packaging provides long term stability for dry vaccine.

The device of FIGURES 1 and 2 is preferably provided With a manipulator, such as a handle, stem, or elongated rod 28 attached to or made integral with the back side of base 20. The cross-section of manipulator 28 may be round or of the same periphery as base 20, as long as it provides a convenient grasp to the user. A preferred form of manipulator is the thumb ring mounting specifically illustrated in FIGURES 547 and generally disclosed in FIG. of U.S. Patent 3,062,212.

In the form of device in FIGURES 5-7, there is provided an integrally molded scarilier and manipulator including a frusto-conical, split ring, thumb mounting 40, with a flattened internal surface 42 for pressure engagement by a thumb pad. The surface 42 is the back side of a circular base 44 having a projecting, smear preventing, platform 46 from whence extend nine (9) pressure puncture points 48. The points 48 in FIGURES 5-7 are clustered more tightly on platform 46 than in FIGURES 1-4, the points 48 being spaced inwardly from the peripheral edge of platform 46.

The length of points 24 and 48 is about 0.21 crn. It is believed that the preferable range of point length is said length plus or minus a few (2 to 5) hundredths of a centimeter. The spacing of the tips of a pair of points 24 in FIGURES 1-4 is about 0.12 cm., while the spacing of the tips of a pair of points 48 in FIGURES 5-7 is -about 0.08 cm. The maximum desirable range of spacing of the tips of a pair of scarifying points to effect desired capillarity, is about 0.12 cm. plus a few hundredths of a centimeter, While theoretically there is no minimum limit to the spacing of the tips, except for the practicality of insuring a suliicient size of crotch 26 to receive and retain an adequate amount of vaccine or other biological therein. In the use of the device, only a single dose of vaccine, or biological, is required to be reconstituted in order to provide a complete instrumentality.

While the forms of device disclosed show use of nine (9) scarifying points, it will be understood that more or less points may be used, although the theoretical considerations set out above for obtaining an eicacious, predictable result that may be duplicated requires at least two scarifying points defining a crotch that may be consistently and uniformly loaded. The loading of points is more economical in the use of vaccine than in previous methods. For example, present single dosage of liquid vaccine carried in a frangible glass tube is approximately 0.03 to 0.05 ml. of vaccine. Only about 0.01 ml. of vaccine is needed to load the nine point device of FIGURES 1-4, less is needed with the device of FIGURES 5-7, and if less points were used, a further reduced volume of liquid vaccine Would be required for loading. Nine pressure points are used in the devices disclosed herein because with that number of points only a single pressure of the instrument is required to effect substantially 100% takes with inants and children. If more pressures, prickings or scratchings are to be effected, the number of scarifying points required may be increased.

The scarifrer points may be made of any desired material, including plastics or metals. Preferably, the scariers are molded from plastic, although steel points could also be used.

While the device herein has been described for use in effecting vaccination against smallpox, it will be readily apparent to those skilled in the art that the device and its method of use may be successfully used in other related elds and with other inocula, such as, for example, in effecting tuberculin testing, use of B C G, and in effecting virus inoculations.

While there has been shown and described -a particular embodiment of this invention, it will be obvious to those skilled in the art that various changes and modications may be made therein without departing from the invention and, therefore, it is intended in the appended claims to cover all such changes and modications as fall within the true spirit and scope of the invention.

What I claim as new, and desired to secure by Letters Patent of the United States, is:

1. In a biological applicator of the type that includes a plurality of at least two scarifying needles projecting from a common support and a solid residue of dried biological substance carried by all said scarifying needles,

0 the improvement comprising:

the plurality of needles and the common support cooperating to define an elongated crotch space extending longitudinally between each pair of needles with one end of the crotch space adjacent the common support and with all the needles of the applicator clustered together, the length of the needles from their common support being in the order of 0.21 cm. and the spacing between the tips of the needles being in the range of 0.08 to 0.12 cm., each needle providing at least one side that bounds said crotch space and which side is inclined along the length of the needle from the tip thereof to said common support so that the width dimension of the crotch space is smaller adjacent the common support than at the tips of the needles,

a dried residue of a single liquid dose of biological substance carried at the common-support end of each crotch space and with the tip end of each needle distal from both the dried residue and the common support and being substantially free of such solid residue,

the combined portions of each crotch space that is free of said dried residue providing a diluent-receivingand-holding space adapted to receive and hold therein an amount of liquid diluent that is retained therein by surface tension between the liquid diluent and the adjacent needles and is suilcient to precisely reconstitute the dried residue located at the other end of the crotch space, thereby providing an applicator that is required to be reconstituted before usage by an amount of liquid diluent to yield an effective and precise liquid dose of biological that is to be administered simultaneously with scarifcation by all the needles of the applicator.

2. A device as set forth in claim 1, wherein the applicator includes at least 3 needles with each needle being common to at least each of two pairs of needles arranged in planes transverse to each other, so as to dene between all the needles a crotch space whose total volume is er1- hanced by a multiplicity of pairs needles acting in concert.

References Cited UNITED STATES PATENTS 652,999 7/ 1900 Denis 128-253 2,619,962 12/ 1952 Rosenthal 128-25-3 3,010,455 11/1961 Cooper 128-253 3,034,507 5/1962 McConnell et al 128--253 3,074,403 1/ 1963 Cooper et al. 128-253 3,123,212 3/1964 Taylor et al. 12S-253 X 3,136,314 6/ 1964 Kravitz 1218-253 3,148,772 9/ 1964 Sair 206-632 3,221,739 12/ 1965 Rosenthal 12S-253 FOREIGN PATENTS 1,309,352 10/ 1962 France.

OTHER REFERENCES A Simplified Technique for Vaccination Against Smallpox, by Harvey Kravitz, reprint from Pediatrics, vol. 27, No. 2, February, 1961, pp. 219-226.

RICHARD A. GAUDET, Primary Examiner. R. L. FRINKS, Assistant Examiner. 

1. IN A BIOLOGICAL APPLICATOR OF THE TYPE THAT INCLUDES A PLURALITY OF AT LEAST TWO SCARIFYING NEEDLES PROJECTING FROM A COMMON SUPPORT AND A SOLID RESIDUE OF DRIED BIOLOGICAL SUBSTANCE CARRIED BY ALL SAID SCARIFYING NEEDLES, THE IMPROVEMENT COMPRISING: THE PLURALITY OF NEEDLES AND THE COMMON SUPPORT COOPERATING TO DEFINE AN ELONGATED CROTCH SPACE EXTENDING LONGITUDINALLY BETWEEN EACH PAIR OF NEEDLES WITH ONE END OF THE CROTCH SPACE ADJACENT THE COMMON SUPPORT AND WITH ALL THE NEEDLES OF THE APPLICAOTR CLUSTERED TOGETHER, THE LENGTH OF THE NEEDLES FROM THEIR COMMON SUPPORT BEING IN THE ORDER OF 0.21 CM. AND THE SPACING BETWEEN THE TIPS OF THE NEEDLES BEING IN THE RANGE OF 0.08 TO 0.12 CM., EACH NEEDLE PROVIDING AT LEAST ONE SIDE THAT BOUNDS SAID CROTCH SPACE AND WHICH SIDE IS INCLINED ALONG THE LENGTH OF THE NEEDLE FROM THE TIP THEREOF OF SAID COMMON SUPPORT SO THAT THE WIDTH DIMENSION OF THE CROTCH SPACE IS SMALLER ADJACENT THE COMMON SUPPORT THAN AT THE TIPS OF THE NEEDLES, A DRIED RESIDUE OF A SINGLE LIQUID DOSE OF BIOLOGICAL SUBSTANCE CARRIED AT THE COMMON-SUPPORT END OF EACH CROTCH SPACE AND WITH THE TIP END OF EACH NEEDLE DISTAL FROM BOTH THE DRIED RESIDUE AND THE COMMON SUPPORT AND BEING SUBSTANTIALLY FREE OF SUCH SOLID RESIDUE, THE COMBINED PORTIONS OF EACH CROTCH SPACE THAT IS FREE OF SAID DRIED RESIDUE PROVIDING A DILUENT-RECEIVINGAND-HOLDING SPACE ADAPTED TO RECEIVE AND HOLD THEREIN AN AMOUNT OF LIQUID DILUENT THAT IS RETAINED THEREIN BY SURFACE TENSION BETWEEN THE LIQUID DILUENT AND THE ADJACENT NEEDLES AND IS SUFFICIENT TO PRECISELY RECONSTITUTE THE DRIED RESIDUE LOCATED AT THE OTHER END OF THE CROTCH SPACE, THEREBY PROVIDING AN APPLICATOR THAT IS REQUIRED TO BE RECONSTITUTED BEFORE USAGE BY AN AMOUNT OF LIQUID DILUENT TO YIELD AN EFFECTIVE AND PRECISE LIQUID DOSE OF BIOLOGICAL THAT IS TO BE ADMINISTERED SIMULTANEOUSLY WITH SCARIFICATION BY ALL THE NEEDLES OF THE APPLICATOR. 